Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
183 mg/m³
DNEL related information
DNEL derivation method:
other: National OEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

N2O – Rationale for determining DNELs

Whilst there is a plenty of animal data available for N2O, the extent of regulatory animal toxicology data for N2O are limited, with current national OELs set from old experimental data. There is extensive information on human volunteer studies at occupationally relevant N2O concentrations, these studies have provided a wealth of data from which OELs have been derived. A search of the literature has revealed that most animal toxicity studies have been done at high doses, usually using prolonged (continuous) exposures to characterise adverse effects of N2O and in some cases to investigate mechanisms of N2O toxicity. Few studies have been designed to define NOAELs for risk assessment purposes. DNELs could be derived from toxicology studies submitted in this dossier; however these would ignore the extensive human data. For example, the lowest dose level in developmental toxicity studies in rats (section 7.8.1) was 500 ppm for teratogenic effects. According to the guidance in Chapter R.8 the following assessment factors (AFs) would be appropriate:

 

Interspecies factor = 2.5 (no correction required for allometric scaling)

Intraspecies factor = 5 for workers

Exposure duration = 1 (24 hours exposure/day during days 1-19 of gestation, therefore no correction required)

Dose-response = 1

Quality of whole database = 1 (this factor could arguably be higher based on quality of the animal toxicity data)

Total AF = 12.5

DNEL = 500/12.5 = 40 ppm
 

This DNEL is comparable to the OEL set for Belgium, Denmark and Spain, but 2.5 fold lower than other EU countries. Lowering the occupational limit to 40 ppm based on a DNEL from animal toxicity data would clearly give an exposure which is much lower than the concentrations reported in dental offices (400 to 1000 ppm). However, OEL below 100 ppm are all based on the effects on performance observed and reported by Bruceet al(1974, 1975). These studies have been severely criticised and despite attempts the results have not been reproduced.
 

In terms of environmental exposure, N2O is ubiquitous in the atmosphere because it is a product of biological processes in soil as well as anthropogenic activities. It is not involved to any appreciable extent in chemical reactions in the lower atmosphere, but it is an active "greenhouse" gas. In the stratosphere N2O forms NO by reaction with excited oxygen atoms, and this NO then acts to deplete the stratospheric O3 concentration.
 

Occupational Exposure Limits

Due to N2O being readily oxidised, elevated concentrations of N2O occur in numerous settings, including those at work, at home or in the street. N2O is not very toxic after acute or repeated exposures. Concentrations of 300000 ppm and more have analgesic effects and 800000 ppm and more have anaesthetic effects. A NOEL of 100000 ppm has been identified for acute CNS distrubance identified by psychometric testing under laboratory conditions (COT, 1995). Three kinds of occupational exposure limits are currently utilized in a number of countries. The most common are: average permissible concentrations for a typical 8 hour working day (time-weighted average, TWA); concentrations for short-term exposures, generally of 15-min duration (short-term exposure limit, STEL); and maximum permissible concentrations not to be exceeded (ceiling limit). This discussion will centre round the justification for a common OEL (TWA and STEL) to take forward for DNEL setting and risk characterisation for the N2O chemical safety report.
 

Discussion of OELs below has been summarised from authoritative reviews of extensive, relevant published literature (EHC, 1997, EIGA, 2008, COT 1995), with a summary of available OELs taken directly from the IFA website.

 

Occupational exposure limits

Country

Limit value – 8 h

Limit value – short term

ppm

mg/m3

ppm

mg/m3

Australia

25

45

 

 

Austria

100

180

400

720

Belgium

50

91

 

 

Denmark

50

90

100

180

EU

 

 

 

 

France

 

 

 

 

Germany

100

180

200

360

Hungary

 

180

 

720

Italy

 

 

 

 

New Zealand

 

 

 

 

Poland

 

90

 

 

Singapore

50

90

 

 

Spain

50

92

 

 

Sweden

100

180

500

900

Switzerland

100

182

200

364

The Netherlands

 

 

 

 

United Kingdom

100

183

 

 

North America and US

Canada (Ontario)

25

45

 

 

Canada (Québec)

50

90

 

 

US – NIOSH

25

46

 

 

Table has been adapted from the IFA Institut fur Arbeitsschutz der Deutschen Gesetzlichen Unfallversicherung (website details included under references) 

 

The UK established the OEL at 100 ppm based on studies relating to developmental toxicity in experimental animals. In relation to this endpoint, the overall NOAEL in the rat was 500 ppm. The probable underlying mechanism for developmental toxicity is impairment of DNA synthesis resulting from inhibition of vitamin B12-dependent methionine synthase. Studies in humans, including limited investigations in dentists indicate consistent mechanism in rodents and humans. Given this toxicological picture, an OEL of 100 ppm (8 h TWA), a factor of 5-fold below the overall NOAEL for developmental toxicity in animals was established by the UK Committee on Toxicity (UK COT, 1995), with Austria, Germany, Sweden and Switzerland concluding the same OEL.

 

Whilst it is recognised that OELs within some European countries and North America / US are below 100 ppm this is based on the effects on performance observed and reported by Bruceet al(1974, 1975). These studies have been severely criticised and despite attempts the results have not been reproduced.
 

The requirement to set a STEL in the UK was not deemed necessary due to the non-toxic nature of N2O.

 

Conclusions on DNEL setting

The use of animal toxicity data on N2O is not appropriate for deriving DNELs. The use of OELs from which to derive DNELs for N2O is considered to be scientifically justified since OELs have been set based on extensive human and animal data.

 

Therefore under guidance from ECHA (2010), as national OELs have already been set by several EU and Non-EU countries for daily inhalation exposure over 8 hours/working day and for acute / short term exposure (15 minutes); relevant DNELs will be derived from these.
 
The proposed UK / Sweden / Germany / Austria OEL for the 8-hour working limit of 100 ppm (180 mg/m3) are are selected as the DNELs for occupational exposure.
 In accordance with ECHA (2010), Chapter R.8 “a DNELfor acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential for high peak exposures.” N2O is considered to be neither acutely toxic (i.e. absence of C&L for this endpoint) and the intended uses will not result in high peak exposures, therefore an acute DNEL is considered unnecessary. Following a review of the latest available data there are no new studies which would negatively impact upon the position that these values are protective with regard to occupational exposure.

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

 In accordance with ECHA (2010), Chapter R.8 “a DNELfor acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential for high peak exposures.” N2O is considered to be neither acutely toxic (i.e. absence of C&L for this endpoint) and the intended uses will not result in high peak exposures, therefore an acute DNEL is considered unnecessary.